Structured Treatment Interruption in HIV Positive Patients. Leah Jackson, BScPhm Pharmacy Resident HIV Rotation January 23, 2007

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1 Structured Treatment Interruption in HIV Positive Patients Leah Jackson, BScPhm Pharmacy Resident HIV Rotation January 23, 2007

2 Objectives To become re-acquainted with the basics of HAART for HIV infection To list reasons why a patient may want to interrupt HAART To describe the appropriateness of structured treatment interruption based on the findings of the SMART study

3 HAART Highly Active Anti-Retroviral Therapy Often involves the use of 3 or more anti- retrovirals (ARVs)) acting at different stages of the HIV life cycle (ie( ie/ / PIs, NNRTIs, NRTIs, etc) Combination therapy provides potent viral suppression leading to good immune system recovery Life-long use HIV now considered a chronic disease

5 Pharmacotherapy basics Protease inhibitors PIs Non-nucleoside nucleoside reverse transcriptase inhibitors NNRTIs Nucleoside reverse transcriptase inhibitors NRTIs Lopinavir/r Fosamprenavir Atazanavir Nelfinavir *Darunavir/r (TMC 114) Efavirenz (EFV) Nevirapine (NVP) *Etravirine (TMC 125) Abacavir (ABC) Lamivudine (3TC) Zidovudine (AZT) Stavudine (d4t) Didanosine (ddi) *Tenofovir (TDF)

6 Other agents Enfuvirtide (fusion inhibitor) Maraviroc, vicriviroc (CCR5 receptor antagonists) MK-0518 (integrase( inhibitor) 2

7 DHHS Guidelines 3

9 Adverse Effects NRTI backbone Nausea Peripheral neuropathy (often d drugs) Lactic acidosis Hepatic steatosis Pancreatitis Lipodystrophy (d4t) Renal insufficiency (TDF) Hypersensitivity (ABC) Bone marrow suppression, headache, insomnia (AZT)

10 Adverse Effects NNRTIs Rash Stevens-Johnson syndrome (esp. NVP) liver transaminases hepatitis, hepatic necrosis CNS effects with EFV (insomnia, abnormal dreams, dizziness, confusion, abnormal thinking, hallucinations.) Teratogenesis (EFV) ++ potential for drug interactions

11 PIs Adverse Effects N/V/D liver transaminases Hyperlipidemia (esp. TG) Hyperglycemia Fat maldistribution Hyperbilirubinemia (atazanavir, indinavir) Nephrolithiasis (indinavir) Oral paresthesia (ritonavir) Intracranial hemorrhage (tipranavir( tipranavir) ++ potential for drug interactions

12 Potential reasons for interruption Adverse events! Pill burden and necessity of adherence Resistance Cost

13 Question: Can we safely interrupt ARV treatment???

14 CD4+ Count-Guided Interruption of Antiretroviral Treatment 4 The SMART study group. NEJM 2006;335: Enrolment began January 2, sites in 33 countries incl. TGH! Ambitious target of 6000 patients Follow-up planned for 6+ years

15 Background Despite morbidity and mortality with HAART, its effectiveness is limited by adverse events (metabolic and cardiovascular complications), problems with adherence, and viral resistance (incl. multi-drug resistance) Lifelong treatment

16 Purpose To study a treatment-sparing strategy in hopes of providing the benefits of ARV therapy while minimizing the adverse events and other risks of long-term use

17 Intervention 5472 patients randomized: Drug conservation arm: episodic drug tx based on CD4 count; start tx if <250, and stop when >350 Viral suppression arm: uninterrupted tx with goal of maximal and continuous suppression of HIV replication (standard care)

18 Inclusion criteria >13 years of age (median age 43) Not pregnant/breastfeeding Eligible whether or not they had received or were currently receiving ARVs (84% on tx at baseline) Willing to initiate, modify or stop ARVs according to the guidelines

19 Case example: CC 44 yo diagnosed at age 38 Sexual transmission (homosexual) At dx: : CD4=620, VL= Started treatment during seroconversion illness EFV and Combivir (AZT/3TC) Numbness in fingertips, mild lipoatrophy,, bad dreams ++ interested in stopping treatment Enrolled in SMART July 2005; CD4 800, VL <50 Randomized to discontinue medications

20 Case example: RC 42 yo diagnosed at age 28 Sexual transmission (heterosexual) ARV history: AZT, AZT/3TC study (impotence, fatigue, h/a, nausea, anemia); ddi; ddc and saquinavir; ; EFV, d4t, nelfinavir 1998-present Has experienced opportunistic infections (OIs( OIs) ) including disseminated zoster Tingling extremities, significant abdominal obesity and buffalo hump, ++ vivid dreams (requires sleeping pill), dyslipidemia (TC 13.48, TG prior to lipid tx) Enrolled in SMART July 2005; CD4 1001, VL <50 Randomized to continue HAART

21 Demographics Similar at baseline, incl. CV risk factors Women (27%), hepatitis B and C co-infection, various races (white 56%, black 29%, other 15%) Median CD4 = 597 VL < 400 in 72% of patients Median 6 years since first ARVs 24% had prior AIDS-related illness 5

22 Monitoring and follow-up Scheduled 1 mo and 2 mos,, q2mos thereafter for 1 st year, then q4mos in 2 nd and subsequent years More frequent if clinical care required Independent data and safety board to review interim analyses at least yearly STOPPED EARLY: mean follow-up only 16 mos; ; 26% of pts followed > 2 years

23 Primary Endpoints New or recurrent opportunistic disease 5,6 or death from any cause Secondary Death from any cause Serious opportunistic disease 7 Major cardiovascular, renal, or hepatic disease 6 Grade 4 adverse events 8 (not incl. opportunistic disease) or death from any cause

24 Results Median duration of 1 st interruption=17 mos N=343 stopped ARVs a 2 nd time N=62 stopped ARVs 3 times CD4 count 87 cells/mm 3 per month x 2 mos, then at lower rate (drug conservation group) CD4 count was 206 cells/mm 3 lower in drug conservation group Within 2 mos,, patients with VL 400 copies/ml from 72% to 6%

25 CD4 count 6 changes

26 % patients with VL 6 400

27 Results After reinitiation of ARVs,, time to VL 400 copies/ml was 3.1 mos CD4 count 166 cells/mm 3 within 8 mos

28 Results Received ARVs (% time) CD4 count 350 (% time) CD4 count < 250 (% time) VL 400 copies/ml (% time) Drug conservation (DC) group 33.4% 67.9% 8.6% 28.8% Viral suppression (VS) group 93.7% 92.7% 1.8% 72.3%

29 Results4

30 Results Hazard ratio (HR) for primary endpoint (opportunistic disease of death from any cause) = 2.6 (95% CI ; P<0.001) Most common individual events DC group: death from any cause (39%), esophageal candidiasis (20%), and PCP (7%) VS group: death from any cause (57%) and esophageal candidiasis (15%)

31 Results Number of deaths = 85 Only 8% due to opportunistic disease Common causes of death outside of opportunistic disease: Cancer (DC>VS) CVD (DC>VS) Substance abuse Accident, violence, or suicide Unknown for 18 patients (15 DC, 3 VS)

32 Results Sensitivity analysis on primary endpoint: New opportunistic disease (OD) or death from any cause HR=2.6 (95% CI , P<0.001) Fatal and non-fatal cases of OD (excl. deaths from other causes) HR=3.6 ( , P<0.001) All reported cases of ODs and deaths irrespective of classification after review by endpoint review committee HR=2.5 (1.9-33, P<0.001) (Note: HR reported for DC group vs VS group)

33 Results Secondary endpoints (DC group vs VS group) Death from any cause: HR=1.8 (95% CI ) 2.9) Serious opportunistic disease: HR=6.6 ( ) Major CV, renal, or hepatic disease: HR=1.7 ( ) Grade 4 event or death from any cause: HR=1.3 ( ) 1.6)

34 Clinical Application Continuous use of ARVs is superior to episodic use guided by the CD4 count thresholds used in the SMART study SMART strategy is deleterious even patients with good CD4 counts are at risk for bad clinical events if not on treatment (outside of ODs as well) Lack of benefit of interruption on major adverse events

35 Clinical Application Interruption strategies should be viewed with net clinical risk unless proven otherwise in properly powered studies

36 Study limitations Overall, very well done! Follow-up missing for 73 patients at the close of the study (32 in interruption group, 41 in suppression group) Unblinded,, but endpoint review committee unaware of treatment assignments Equal treatment of groups? Concomitant diseases and medications unknown, including use of OI treatment and prophylaxis

37 Unanswered questions Is it possible to safely interrupt treatment at higher CD4 thresholds? Smaller studies have attempted to answer some of them Staccato 9 (n=284) deferred treatment until CD4 < 350; compared to continuous tx,, more oral and vaginal candidiasis

38 Case examples Mr CC: Discontinued meds (EFV/Combivir Combivir) ) July 2005 as per SMART randomization; very pleased about this Study closed January 2006; CD4 count 912, VL still <50 Did not resume medications upon study closure

39 Case examples Mr. RC: Long ARV history; randomized to continue medications in July 2005 as per SMART study Remains on d4t, nelfinavir,, EFV (since 1998) Lipids controlled on pravastatin and fenofibrate (TG 2.5 recently vs in 2002) Difficulty with weight loss despite exercise

40 References 1. Egger M, May M, Chêne G, et al. Prognosis of HIV-1-infected patients starting highly active antiretroviral therapy: a collaborative analysis of prospective studies. Lancet 2002;360: Integrase article 3. DHHS Panel of the Office of AIDS Research Advisory Council. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Infected Adults and Adolescents. October 10, The SMART study group. CD4+ Count-Guided Interruption of Antiretroviral Treatment. NEJM 2006;255: Revised classification system for HIV infection and expanded d surveillance case definition for AIDS among adolescents and adults. MMWR Recomm Rep 1992;41:No. RR-17:1 17: html1992.html 6. Supplementary web-only appendix for SMART study available through fulltext article at 7. Neaton JD, Wentworth DN, Rhame F, et al. Considerations in choice of a clinical endpoint for AIDS clinical trials (CPCRA). Stat Med 1994;13: Adaptation of toxicity table of the Division of AIDS of the NIAID. Accessed online at 9. Ananworanich J, Gayet-Ageron A, Le Braz M, et al. CD4-guided scheduled treatment interruptions compared with continuous therapy for patients infected with HIV-1: results of the Staccato randomised trial. Lancet 2006;368:

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